This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sowter, H. M. Articles by Harris, A. L. Search for Related Content PubMed PubMed Citation Articles by Sowter, H. M. Articles by Harris, A. L.

Predominant Role of Hypoxia-Inducible Transcription Factor (Hif)-1 versus Hif-2 in Regulation of the Transcriptional Response to Hypoxia¹

Cancer Research UK, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DU [H. M. S., J. M., A. L. H.], and Wellcome Trust Centre for Human Genetics, Oxford OX3 7BN [R. R., P. J. R.], United Kingdom

Tumor hypoxia induces the up-regulation of a gene program associated with angiogenesis, glycolysis, adaptation to pH, and apoptosis via the hypoxia-inducible transcription factors (Hifs) 1 and 2. Disruption of this pathway has been proposed as a cancer therapy. Here, we use short interfering RNAs to compare specific inactivation of Hif-1 or Hif-2 and show markedly different cell type-specific effects on gene expression and cell migration. Remarkably, among a panel of hypoxia-inducible genes, responses were critically dependent on Hif-1 but not Hif-2 in both endothelial and breast cancer cells but critically dependent on Hif-2 in renal carcinoma cells.

This article has been cited by other articles:

				A. Taguchi, K. Yanagisawa, M. Tanaka, K. Cao, Y. Matsuyama, H. Goto, and T. Takahashi Identification of Hypoxia-Inducible Factor-1{alpha} as a Novel Target for miR-17-92 MicroRNA Cluster Cancer Res., July 15, 2008; 68(14): 5540 - 5545. [Abstract] [Full Text] [PDF]

				A. Basu, A. G. Contreras, D. Datta, E. Flynn, L. Zeng, H. T. Cohen, D. M. Briscoe, and S. Pal Overexpression of Vascular Endothelial Growth Factor and the Development of Post-Transplantation Cancer Cancer Res., July 15, 2008; 68(14): 5689 - 5698. [Abstract] [Full Text] [PDF]

				S. A. Gerber and J. S. Pober IFN-{alpha} Induces Transcription of Hypoxia-Inducible Factor-1{alpha} to Inhibit Proliferation of Human Endothelial Cells J. Immunol., July 15, 2008; 181(2): 1052 - 1062. [Abstract] [Full Text] [PDF]

				T. Yamashita, K. Ohneda, M. Nagano, C. Miyoshi, N. Kaneko, Y. Miwa, M. Yamamoto, O. Ohneda, and Y. Fujii-Kuriyama Hypoxia-inducible Transcription Factor-2{alpha} in Endothelial Cells Regulates Tumor Neovascularization through Activation of Ephrin A1 J. Biol. Chem., July 4, 2008; 283(27): 18926 - 18936. [Abstract] [Full Text] [PDF]

				M. Puppo, F. Battaglia, C. Ottaviano, S. Delfino, D. Ribatti, L. Varesio, and M. C. Bosco Topotecan inhibits vascular endothelial growth factor production and angiogenic activity induced by hypoxia in human neuroblastoma by targeting hypoxia-inducible factor-1{alpha} and -2{alpha} Mol. Cancer Ther., July 1, 2008; 7(7): 1974 - 1984. [Abstract] [Full Text] [PDF]

				K. J. Champion, M. Guinea, V. Dammai, and T. Hsu Endothelial Function of von Hippel-Lindau Tumor Suppressor Gene: Control of Fibroblast Growth Factor Receptor Signaling Cancer Res., June 15, 2008; 68(12): 4649 - 4657. [Abstract] [Full Text] [PDF]

				R. Seifeddine, A. Dreiem, E. Blanc, M.-C. Fulchignoni-Lataud, M.-A. L. F. Belda, F. Lecuru, T. H. Mayi, N. Mazure, V. Favaudon, C. Massaad, et al. Hypoxia Down-regulates CCAAT/Enhancer Binding Protein-{alpha} Expression in Breast Cancer Cells Cancer Res., April 1, 2008; 68(7): 2158 - 2165. [Abstract] [Full Text] [PDF]

				F. Battaglia, S. Delfino, E. Merello, M. Puppo, R. Piva, L. Varesio, and M. C. Bosco Hypoxia transcriptionally induces macrophage-inflammatory protein-3{alpha}/CCL-20 in primary human mononuclear phagocytes through nuclear factor (NF)-{kappa}B J. Leukoc. Biol., March 1, 2008; 83(3): 648 - 662. [Abstract] [Full Text] [PDF]

				V. A. Carroll and M. Ashcroft Regulation of Angiogenic Factors by HDM2 in Renal Cell Carcinoma Cancer Res., January 15, 2008; 68(2): 545 - 552. [Abstract] [Full Text] [PDF]

				S. Sathornsumetee, Y. Cao, J. E. Marcello, J. E. Herndon II, R. E. McLendon, A. Desjardins, H. S. Friedman, M. W. Dewhirst, J. J. Vredenburgh, and J. N. Rich Tumor Angiogenic and Hypoxic Profiles Predict Radiographic Response and Survival in Malignant Astrocytoma Patients Treated With Bevacizumab and Irinotecan J. Clin. Oncol., January 10, 2008; 26(2): 271 - 278. [Abstract] [Full Text] [PDF]

				L. K. Martens, K. M. Kirschner, C. Warnecke, and H. Scholz Hypoxia-inducible Factor-1 (HIF-1) Is a Transcriptional Activator of the TrkB Neurotrophin Receptor Gene J. Biol. Chem., May 11, 2007; 282(19): 14379 - 14388. [Abstract] [Full Text] [PDF]

				I. Kojima, T. Tanaka, R. Inagi, H. Kato, T. Yamashita, A. Sakiyama, O. Ohneda, N. Takeda, M. Sata, T. Miyata, et al. Protective Role of Hypoxia-Inducible Factor-2{alpha} against Ischemic Damage and Oxidative Stress in the Kidney J. Am. Soc. Nephrol., April 1, 2007; 18(4): 1218 - 1226. [Abstract] [Full Text] [PDF]

				T. Shinojima, M. Oya, A. Takayanagi, R. Mizuno, N. Shimizu, and M. Murai Renal cancer cells lacking hypoxia inducible factor (HIF)-1{alpha} expression maintain vascular endothelial growth factor expression through HIF-2{alpha} Carcinogenesis, March 1, 2007; 28(3): 529 - 536. [Abstract] [Full Text] [PDF]

				D. Viemann, M. Schmidt, K. Tenbrock, S. Schmid, V. Muller, K. Klimmek, S. Ludwig, J. Roth, and M. Goebeler The Contact Allergen Nickel Triggers a Unique Inflammatory and Proangiogenic Gene Expression Pattern via Activation of NF-{kappa}B and Hypoxia-Inducible Factor-1{alpha} J. Immunol., March 1, 2007; 178(5): 3198 - 3207. [Abstract] [Full Text] [PDF]

				J. An and M. B. Rettig Epidermal growth factor receptor inhibition sensitizes renal cell carcinoma cells to the cytotoxic effects of bortezomib Mol. Cancer Ther., January 1, 2007; 6(1): 61 - 69. [Abstract] [Full Text] [PDF]

				T. M. Asikainen, N. S. Waleh, B. K. Schneider, R. I. Clyman, and C. W. White Enhancement of angiogenic effectors through hypoxia-inducible factor in preterm primate lung in vivo Am J Physiol Lung Cell Mol Physiol, October 1, 2006; 291(4): L588 - L595. [Abstract] [Full Text] [PDF]

				R. D. Guzy and P. T. Schumacker Oxygen sensing by mitochondria at complex III: the paradox of increased reactive oxygen species during hypoxia Exp Physiol, September 1, 2006; 91(5): 807 - 819. [Abstract] [Full Text] [PDF]

				S. Kaluz, M. Kaluzova, and E. J. Stanbridge Proteasomal Inhibition Attenuates Transcriptional Activity of Hypoxia-Inducible Factor 1 (HIF-1) via Specific Effect on the HIF-1{alpha} C-Terminal Activation Domain Mol. Cell. Biol., August 1, 2006; 26(15): 5895 - 5907. [Abstract] [Full Text] [PDF]

				M. A. Esteban, S. K. Harten, M. G. Tran, and P. H. Maxwell Formation of Primary Cilia in the Renal Epithelium Is Regulated by the von Hippel-Lindau Tumor Suppressor Protein J. Am. Soc. Nephrol., July 1, 2006; 17(7): 1801 - 1806. [Abstract] [Full Text] [PDF]

				X. Zheng, J. L. Ruas, R. Cao, F. A. Salomons, Y. Cao, L. Poellinger, and T. Pereira Cell-Type-Specific Regulation of Degradation of Hypoxia-Inducible Factor 1{alpha}: Role of Subcellular Compartmentalization Mol. Cell. Biol., June 15, 2006; 26(12): 4628 - 4641. [Abstract] [Full Text] [PDF]

				V. A. Carroll and M. Ashcroft Role of Hypoxia-Inducible Factor (HIF)-1{alpha} versus HIF-2{alpha} in the Regulation of HIF Target Genes in Response to Hypoxia, Insulin-Like Growth Factor-I, or Loss of von Hippel-Lindau Function: Implications for Targeting the HIF Pathway. Cancer Res., June 15, 2006; 66(12): 6264 - 6270. [Abstract] [Full Text] [PDF]

				G. P. Elvidge, L. Glenny, R. J. Appelhoff, P. J. Ratcliffe, J. Ragoussis, and J. M. Gleadle Concordant Regulation of Gene Expression by Hypoxia and 2-Oxoglutarate-dependent Dioxygenase Inhibition: THE ROLE OF HIF-1{alpha}, HIF-2{alpha}, AND OTHER PATHWAYS J. Biol. Chem., June 2, 2006; 281(22): 15215 - 15226. [Abstract] [Full Text] [PDF]

				H. Okuyama, B. Krishnamachary, Y. F. Zhou, H. Nagasawa, M. Bosch-Marce, and G. L. Semenza Expression of Vascular Endothelial Growth Factor Receptor 1 in Bone Marrow-derived Mesenchymal Cells Is Dependent on Hypoxia-inducible Factor 1 J. Biol. Chem., June 2, 2006; 281(22): 15554 - 15563. [Abstract] [Full Text] [PDF]

				O. Aprelikova, M. Wood, S. Tackett, G. V.R. Chandramouli, and J. C. Barrett Role of ETS Transcription Factors in the Hypoxia-Inducible Factor-2 Target Gene Selection Cancer Res., June 1, 2006; 66(11): 5641 - 5647. [Abstract] [Full Text] [PDF]

				M. A. Esteban, M. G.B. Tran, S. K. Harten, P. Hill, M. C. Castellanos, A. Chandra, R. Raval, T. S. O'Brien, and P. H. Maxwell Regulation of E-cadherin Expression by VHL and Hypoxia-Inducible Factor. Cancer Res., April 1, 2006; 66(7): 3567 - 3575. [Abstract] [Full Text] [PDF]

				F. Dayan, D. Roux, M. C. Brahimi-Horn, J. Pouyssegur, and N. M. Mazure The Oxygen Sensor Factor-Inhibiting Hypoxia-Inducible Factor-1 Controls Expression of Distinct Genes through the Bifunctional Transcriptional Character of Hypoxia-Inducible Factor-1{alpha}. Cancer Res., April 1, 2006; 66(7): 3688 - 3698. [Abstract] [Full Text] [PDF]

				H. J. Knowles, D. R. Mole, P. J. Ratcliffe, and A. L. Harris Normoxic Stabilization of Hypoxia-Inducible Factor-1{alpha} by Modulation of the Labile Iron Pool in Differentiating U937 Macrophages: Effect of Natural Resistance-Associated Macrophage Protein 1. Cancer Res., March 1, 2006; 66(5): 2600 - 2607. [Abstract] [Full Text] [PDF]

				M. I. Koukourakis, S. M. Bentzen, A. Giatromanolaki, G. D. Wilson, F. M. Daley, M. I. Saunders, S. Dische, E. Sivridis, and A. L. Harris Endogenous Markers of Two Separate Hypoxia Response Pathways (hypoxia inducible factor 2 alpha and carbonic anhydrase 9) Are Associated With Radiotherapy Failure in Head and Neck Cancer Patients Recruited in the CHART Randomized Trial J. Clin. Oncol., February 10, 2006; 24(5): 727 - 735. [Abstract] [Full Text] [PDF]

				K. D. Cowden Dahl, B. H. Fryer, F. A. Mack, V. Compernolle, E. Maltepe, D. M. Adelman, P. Carmeliet, and M. C. Simon Hypoxia-Inducible Factors 1{alpha} and 2{alpha} Regulate Trophoblast Differentiation Mol. Cell. Biol., December 1, 2005; 25(23): 10479 - 10491. [Abstract] [Full Text] [PDF]

				G. L. Semenza Involvement of Hypoxia-Inducible Factor 1 in Pulmonary Pathophysiology Chest, December 1, 2005; 128(6_suppl): 592S - 594S. [Abstract] [Full Text] [PDF]

				G. L. Semenza Involvement of Hypoxia-Inducible Factor 1 in Pulmonary Pathophysiology Chest, December 1, 2005; 128(6_suppl): 592S - 594S. [Abstract] [Full Text] [PDF]

				J. E. Sears and G. Hoppe Triamcinolone Acetonide Destabilizes VEGF mRNA in Muller Cells under Continuous Cobalt Stimulation Invest. Ophthalmol. Vis. Sci., November 1, 2005; 46(11): 4336 - 4341. [Abstract] [Full Text] [PDF]

				N. S. Patel, J.-L. Li, D. Generali, R. Poulsom, D. W. Cranston, and A. L. Harris Up-regulation of Delta-like 4 Ligand in Human Tumor Vasculature and the Role of Basal Expression in Endothelial Cell Function Cancer Res., October 1, 2005; 65(19): 8690 - 8697. [Abstract] [Full Text] [PDF]

				R. Bilton, N. Mazure, E. Trottier, M. Hattab, M.-A. Dery, D. E. Richard, J. Pouyssegur, and M. C. Brahimi-Horn Arrest-defective-1 Protein, an Acetyltransferase, Does Not Alter Stability of Hypoxia-inducible Factor (HIF)-1{alpha} and Is Not Induced by Hypoxia or HIF J. Biol. Chem., September 2, 2005; 280(35): 31132 - 31140. [Abstract] [Full Text] [PDF]

				J. An and M. B. Rettig Mechanism of von Hippel-Lindau Protein-Mediated Suppression of Nuclear Factor kappa B Activity Mol. Cell. Biol., September 1, 2005; 25(17): 7546 - 7556. [Abstract] [Full Text] [PDF]

				R. R. Raval, K. W. Lau, M. G. B. Tran, H. M. Sowter, S. J. Mandriota, J.-L. Li, C. W. Pugh, P. H. Maxwell, A. L. Harris, and P. J. Ratcliffe Contrasting Properties of Hypoxia-Inducible Factor 1 (HIF-1) and HIF-2 in von Hippel-Lindau-Associated Renal Cell Carcinoma Mol. Cell. Biol., July 1, 2005; 25(13): 5675 - 5686. [Abstract] [Full Text] [PDF]

				K. Smith, L. Gunaratnam, M. Morley, A. Franovic, K. Mekhail, and S. Lee Silencing of Epidermal Growth Factor Receptor Suppresses Hypoxia-Inducible Factor-2-Driven VHL-/- Renal Cancer Cancer Res., June 15, 2005; 65(12): 5221 - 5230. [Abstract] [Full Text] [PDF]

				E. B. Rankin, D. F. Higgins, J. A. Walisser, R. S. Johnson, C. A. Bradfield, and V. H. Haase Inactivation of the Arylhydrocarbon Receptor Nuclear Translocator (Arnt) Suppresses von Hippel-Lindau Disease-Associated Vascular Tumors in Mice Mol. Cell. Biol., April 15, 2005; 25(8): 3163 - 3172. [Abstract] [Full Text] [PDF]

				V. Wang, D. A. Davis, M. Haque, L. E. Huang, and R. Yarchoan Differential Gene Up-Regulation by Hypoxia-Inducible Factor-1{alpha} and Hypoxia-Inducible Factor-2{alpha} in HEK293T Cells Cancer Res., April 15, 2005; 65(8): 3299 - 3306. [Abstract] [Full Text] [PDF]

				K. L. Covello, M. C. Simon, and B. Keith Targeted Replacement of Hypoxia-Inducible Factor-1{alpha} by a Hypoxia-Inducible Factor-2{alpha} Knock-in Allele Promotes Tumor Growth Cancer Res., March 15, 2005; 65(6): 2277 - 2286. [Abstract] [Full Text] [PDF]

				V. A.J. Kempf, M. Lebiedziejewski, K. Alitalo, J.-H. Walzlein, U. Ehehalt, J. Fiebig, S. Huber, B. Schutt, C. A. Sander, S. Muller, et al. Activation of Hypoxia-Inducible Factor-1 in Bacillary Angiomatosis: Evidence for a Role of Hypoxia-Inducible Factor-1 in Bacterial Infections Circulation, March 1, 2005; 111(8): 1054 - 1062. [Abstract] [Full Text] [PDF]

				G Eisenhofer, T-T Huynh, K Pacak, F M Brouwers, M M Walther, W M Linehan, P J Munson, M Mannelli, D S Goldstein, and A G Elkahloun Distinct gene expression profiles in norepinephrine- and epinephrine-producing hereditary and sporadic pheochromocytomas: activation of hypoxia-driven angiogenic pathways in von Hippel-Lindau syndrome Endocr. Relat. Cancer, December 1, 2004; 11(4): 897 - 911. [Abstract] [Full Text] [PDF]

				I. P. Stolze, Y.-M. Tian, R. J. Appelhoff, H. Turley, C. C. Wykoff, J. M. Gleadle, and P. J. Ratcliffe Genetic Analysis of the Role of the Asparaginyl Hydroxylase Factor Inhibiting Hypoxia-inducible Factor (HIF) in Regulating HIF Transcriptional Target Genes J. Biol. Chem., October 8, 2004; 279(41): 42719 - 42725. [Abstract] [Full Text] [PDF]

				T. Acker and H. Acker Cellular oxygen sensing need in CNS function: physiological and pathological implications J. Exp. Biol., August 15, 2004; 207(18): 3171 - 3188. [Abstract] [Full Text] [PDF]

				G. L. Semenza Hydroxylation of HIF-1: Oxygen Sensing at the Molecular Level Physiology, August 1, 2004; 19(4): 176 - 182. [Abstract] [Full Text] [PDF]

				N. Takeda, K. Maemura, Y. Imai, T. Harada, D. Kawanami, T. Nojiri, I. Manabe, and R. Nagai Endothelial PAS Domain Protein 1 Gene Promotes Angiogenesis Through the Transactivation of Both Vascular Endothelial Growth Factor and Its Receptor, Flt-1 Circ. Res., July 23, 2004; 95(2): 146 - 153. [Abstract] [Full Text] [PDF]

				T. Uchida, F. Rossignol, M. A. Matthay, R. Mounier, S. Couette, E. Clottes, and C. Clerici Prolonged Hypoxia Differentially Regulates Hypoxia-inducible Factor (HIF)-1{alpha} and HIF-2{alpha} Expression in Lung Epithelial Cells: IMPLICATION OF NATURAL ANTISENSE HIF-1{alpha} J. Biol. Chem., April 9, 2004; 279(15): 14871 - 14878. [Abstract] [Full Text] [PDF]

				M. Zimmer, D. Doucette, N. Siddiqui, and O. Iliopoulos Inhibition of Hypoxia-Inducible Factor Is Sufficient for Growth Suppression of VHL-/- Tumors Mol. Cancer Res., February 1, 2004; 2(2): 89 - 95. [Abstract] [Full Text] [PDF]